1. Field of the Invention
The present invention relates to a process for preparing substituted 1,4-quinone methides of the formula (I) from 3,5-disubstituted 4-hydroxybenzaldehydes, and also to a process for preparing the 3,5-disubstituted 4-hydroxybenzaldehydes from the corresponding 2,6-disubstituted phenols.
2. Description of the Related Art
7-Methoxy- and 7-ethoxy-substituted 1,4-quinone methides are known in the literature as important isolable intermediates for the synthesis of active pharmaceutical ingredients. In addition, some 1,4-quinone methides can be used to prevent undesired polymerization of olefinically unsaturated monomers.
The preparation of 2,6-di-tert-butyl-4-methoxy-methylenecyclohexane-2,5-dienone and of 2,6-di-tert-butyl-4-ethoxymethylenecyclohexane-2,5-dienone is described by Inagaki et al. both in J. Org. Chem. 2002, 67, 125-128 and in EP 0 626 377 A1. This involves reacting a mixture of 3,5-di-tert-butyl-4-hydroxy-benzaldehyde with an excess of trimethyl orthoformate, absolute methanol and xylene in the presence of ammonium chloride as a catalyst to give the corresponding acetal, by heating the reaction mixture under reflux for a few hours. Subsequently, a distillation is performed, xylene is added as an additional solvent, the mixture is cooled, and then the catalyst—the ammonium chloride—is filtered off. In order to achieve the elimination of the alcohol from the acetal to give the substituted 1,4-quinone methide, in both publications, the filtrate is heated and thus methanol and xylene are distilled off. This concentrates the product, which is filtered and then recrystallized in hexane or in a mixture of petroleum ether and ligroin.
The preparation of the corresponding acetal of the 3,5-disubstituted 4-hydroxybenzaldehyde by reaction with orthoformate and/or alcohols is described in numerous publications:
Orlando describes, in J. Org. Chem. 1970, 35, 3714-3717, an almost identical process for preparing the acetal to that of Inagaki et al. in their two publications. Here too, 3,5-di-tert-butyl-4-hydroxybenzaldehyde is heated under reflux with an excess of trimethyl orthoformate and absolute methanol in the presence of ammonium chloride as a catalyst, although no additional solvent is used in this process. After the filtration, the acetal is isolated by concentration and recrystallization from hexane.
Roth et al. described, in J. Med. Chem. 1988, 31, 122-129, a process for preparing the acetal from 3,5-disubstituted 4-hydroxybenzaldehydes, which also involves heating a mixture of 3,5-diisopropyl-4-hydroxybenzaldehyde, trimethyl orthoformate, ammonium chloride and methanol under reflux for a few hours. Subsequently, the reaction mixture is allowed to cool, an aqueous ammonium hydroxide solution is added, the mixture is extracted with dichloromethane and washed, and the organic phase is dried and concentrated to dryness. The desired acetal can then be crystallized from hot hexane.
The preparation of acetals of other 4-hydroxybenzaldehydes with trimethyl orthoformate and/or methanol in the presence of various catalysts is described in numerous publications. For instance, Du et al. describe, in Synthetic Communications 2005, 35, 2703-2708, the use of ionic liquids as a catalyst. The use of amidosulphonic acid as a catalyst is described by Gong et al. in Synthetic Communications 2004, 34, 4243-4247. Lithium tetrafluoroborate as a suitable catalyst is described by Hamada et al. in Synlett 2004, 6, 1074-1076. While Ranu et al. describe the use of indium chloride as a catalyst in Adv. Synth. Catal. 2004, 346(4), 446-450. Gopinath et al. describe, in J. Org. Chem. 2002, 67, 5842-5845, a process for preparing the acetal in the presence of tetrabutylammonium chloride as a catalyst. The use of the highly toxic decaborane as a catalyst is described by Lee et al. in Tetrahedron Letters 2002, 43, 2699-2703. A copolymer with gallium trichloride as suitable catalyst is described by Ruicheng et al. in J. Macromol. Sci.-Chem. 1987, A24(6), 669-679.
The literature describes many different ways of preparing 3,5-substituted 4-hydroxybenzaldehydes. The main starting materials here are the corresponding 2,6-disubstituted phenols or 2,6-disubstituted 4-methylphenols. One method of preparing these 3,5-substituted 4-hydroxybenzaldehydes is the formylation of the 2,6-disubstituted phenols in the para position with urotropin.
For instance, Bolli et al. described, in the two PCT publications, WO 2006/100633 A1 and WO 2006/010544 A2, the reaction of, respectively, 2-ethyl-6-methylphenol and 2,6-diethylphenol with an excess of urotropin in the presence of acetic acid. After distilling off a first solvent fraction, the reaction mixture is heated under reflux for three hours and diluted with water, and then the corresponding 4-hydroxybenzaldehyde is extracted with ethyl acetate. The yields reported are 31% and 40% respectively.
Unangst et al. described, in J. Med. Chem. 1994, 37, 322-328, the reaction of 3,5-diphenylphenol with an excess of urotropin in the presence of acetic acid. This reaction involves adding water, heating the reaction mixture under reflux and removing distillate until a temperature of 114° C. is achieved. The reported yield is 64%.
A process with a yield of 81% is described by Roth et al. in J. Med. Chem. 1988, 31, 122-129. Here, 3,5-diisopropylphenol is reacted with an excess of urotropin in the presence of glacial acetic acid and water. According to the described method, a distillate is removed before the reaction mixture is heated under reflux.